Due to the progress of gene analysis of cytokines and cell adhesion factors, it has been revealed that these substances are controlled by variety of transcription factors (also called as transcription regulatory factors)
STAT (Signal Transduction and Activator of Transcription) is an intracellular protein containing an SH2 (Src Homology 2) region and transmits signals from cytokine receptor into nucleus, and functions per se as an anscriptional factor. Among STAT proteins, STAT6 is known as an important transcriptional factor transmitting signals of interleukin-4 (IL-4) and interleukin-13 (IL-13). STAT6 is bound to GYKXF (SEQ ID NO: 3) motif of IL-4 receptor α chain (IL-4R α) which is a constituting factor of IL-4 receptor and IL-13 receptor, and a JAK family kinase is also bound to these receptors. When IL-4 or IL-13 is bound to a receptor, STAT6 is dimerized by undergoing tyrosine-phosphorylation by the JAK family kinase and translocated into the nucleus where it exerts a function as the transcription factor (refer to Non-patent Documents 1-7).
It is known that IL-4 and IL-13 are related to allergic diseases such as asthma (refer to Non-Patent Documents 3, 4, 5 and 8). Therefore, inhibition of activation of STAT6 is considered to be effective for prophylactic and/or therapeutic treatment of diseases caused by an activation of STAT6.
NF-κB (Nuclear Factor-κB) belongs to a family of closely related homodimeric or heterodimeric transcriptional factor complexes consisting of various combinations of the Rel/NF-KB family of polypeptides. In most cell types, NF-κB exists as a heterodimer (p50/RelA) comprising a 50 kDa and a 65 kDa subunit. The heterodimer is sequestered in the cytoplasm in association with inhibitor of NF-κB (IκB) family of proteins to be kept in an inactive state. Upon stimulation of cells with cytokines (for example, tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1)), CD40 ligand, lipopolysaccharide (LPS), oxidants, mitogens (for example, phorbol ester), viruses, ultraviolet, or the like, IκB proteins are phosphorylated at specific serine residues, poly-ubiquitinated, and then degraded through a proteasome-dependent pathway. Activated form of NF-κB separated from IκB immediately move into nucleus, and exhibits functions as a transcription factor by binding to promoter region which has recognition sequence of NF-κB. Examples of genes of which expressions are under the control with NF-κB include, for example, inflammatory cytokines (for example, IL-1, interleukin-6 (IL-6), interleukin-8 (IL-8) and TNF-α), cell adhesion molecules (for example, intracellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin) and inducible nitric oxide synthase (iNOS) (see, Non-Patent Documents 9-14).
It is known that NF-κB is related to various kinds of diseases (see, Non-Patent Documents 15 and 16). Therefore, inhibition of activation of NF-κB is considered to be effective for prophylactic and/or therapeutic treatment of diseases caused by an activation of NF-κB.
As for salicylanilide compounds wherein the benzene ring which binds to the nitrogen atom is 3,4-disubstituted, and wherein the substituent in the 4-position is a group including a C5-7 cycloalkyl group, a substituted C5-7 cycloalkyl group, a 5 to 7-membered completely saturated heterocyclic group or a substituted 5 to 7-membered completely saturated heterocyclic group, they compounds are described in Patent Document 1 and Non-Patent Documents 17 and 18. However, the compounds encompassed within the scope of the present invention are not described in these documents. Furthermore, these documents do not disclose any information of inhibitory activity against activation of STAT6 and/or NF-κB, and the intended uses of the compounds described in the aforementioned documents are completely different from those of the present invention.
As for compounds having inhibitory activity against activation of STAT6, such compounds are described in, for example, Patent Documents 2-14. However, the compounds described in these documents have completely different chemical structures from those of the compounds of the present invention.
As for compounds having inhibitory activity against activation of NF-κB, such compounds are described in, for example, Patent Documents 15-18. However, the specific compounds encompassed within the present invention are not described in those documents. Furthermore, these documents do not describe any information about the inhibitory activity against activation of STAT6.
[Patent Document 1] The pamphlet of International Publication No. WO94/01113
[Patent Document 2] Japanese Patent Unexamined Publication (KOKAI) No. 10-175964
[Patent Document 3] Japanese Patent Unexamined Publication (KOKAI) No. 10-175965
[Patent Document 4] Japanese Patent Unexamined Publication (KOKAI) No. 11-029475
[Patent Document 5] Japanese Patent Unexamined Publication (KOKAI) No. 11-106340
[Patent Document 6] Japanese Patent Unexamined Publication (KOKAI) No. 11-116481
[Patent Document 7] Japanese Patent Unexamined Publication (KOKAI) No. 2000-229959
[Patent Document 8] The pamphlet of International Publication No. WO02/14321
[Patent Document 9] The pamphlet of International Publication No. WO02/38107
[Patent Document 10] U.S. Patent Application Publication No. US 2005/0227959
[Patent Document 11] European Patent Publication No. EP 1346987
[Patent Document 12] European Patent Publication No. EP 1377553
[Patent Document 13] European Patent Publication No. EP 1382603
[Patent Document 14] European Patent Publication No. EP 1518855
[Patent Document 15] European Patent Publication No. EP 1085848
[Patent Document 16] European Patent Publication No. EP 1314712
[Patent Document 17] European Patent Publication No. EP 1352650
[Patent Document 18] European Patent Publication No. EP 1535609
[Non-Patent Document 1] Science, vol. 264, No. 5164, pp. 1415-1421 (1994).
[Non-Patent Document 2] Immunity, vol. 2, No. 4, pp. 331-339 (1995).
[Non-Patent Document 3] Pharmacol. Ther., vol. 88, No. 2, pp. 143-151 (2000).
[Non-Patent Document 4] J. Immunol., vol. 157, No. 8, pp. 3220-3222 (1996).
[Non-Patent Document 5] J. Immunol., vol. 166, No. 8, pp. 3542-3548 (2001).
[Non-Patent Document 6] Nature, vol. 380, No. 6575, pp. 630-633 (1996).
[Non-Patent Document 7] Science, vol. 265, No. 5179, pp. 1701-1706 (1994).
[Non-Patent Document 8] Clin. Exp. Allergy, vol. 29, No. 1, pp. 114-123 (1999).
[Non-Patent Document 9] Nucl. Acids Res., vol. 14, No. 20, pp. 7898-7914 (1986).
[Non-Patent Document 10] Cold Spring Harb. Symp. Quant. Biol., vol. 51, Pt. 1, pp. 611-624 (1986).
[Non-Patent Document 11] Ann. Rev. Immunol., vol. 14, pp. 649-681 (1996).
[Non-Patent Document 12] Genes Dev., vol. 9, No. 22, pp. 2723-2735 (1995).
[Non-Patent Document 13] Ann. Rev. Immunol., vol. 12, pp. 141-179 (1994).
[Non-Patent Document 14] Cell, Vol. 87, No. 1, pp. 13-20 (1996).
[Non-Patent Document 15] J. Mol. Med., vol. 82, No. 7, pp. 434-448 (2004).
[Non-Patent Document 16] J. Clin. Invest., vol. 107, No. 1, pp. 3-6 (2001).
[Non-Patent Document 17] J. Med. Chem., vol. 20, No. 6, pp. 826-829 (1977).
[Non-Patent Document 18] Ind. J. Exp. Biol., vol. 14, No. 3, pp. 332-333 (1976).